The researchers initially identified 966 significant genes (p<0.05) that contained two or more variants associated with bipolar disorder in at least three of the four genome-wide association studies (comprising 5253 bipolar cases and 6874 controls without bipolar disorder) analysed.

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Of these, 226 genes were classed as empirically significant using a linear regression model and were selected for pathway analysis. This subsequently identified 17 significant pathways that were tested in a replication dataset (n=3507 cases and 4889 controls).

The replication analysis highlighted the six pathways that were significantly overrepresented in the patients with bipolar disorder in both datasets.

They add that the corticotropin-releasing hormone signalling pathway had the strongest association, statistically, with bipolar disorder. This pathway is an index of the hypothalamic-pituitary-adrenal system, a stress response system that is consistently dysregulated in studies of mood disorder, they note.

Further analysis of the datasets showed that 16 genes, including those involved in hormone regulation and second messenger systems, as well as calcium channel and glutamate receptor genes, drove the six significant pathways. Three of these genes – CACNA1C, GNG2 and ITPR2 – are known to have dysregulated expression in the frontal cortex of patients with bipolar disorder.

In addition, the researchers identified nine genes (CACNA1C, DTNA, FOXP1, GNG2, ITPR2, LSAMP, NPAS3, NCOA2 and NTRK3), some of which are involved in neuronal development, that overlapped with genes previously shown to be differentially expressed between people with bipolar disorder and those without.

Nurnberger et al conclude that their results “tend to reinforce specific hypotheses regarding [bipolar disorder] neurobiology and may provide clues for new approaches to treatment and prevention.”

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